The present invention is generally in the area of treating infertility in females and disorders involving steroidal overproduction, such as Cushings' disease, or disorders which can be treated by lowering steroid levels, such as endometriosis and breast and prostate cancer, by altering lipid levels and uptake of cholesterol and other lipids via the SR-BI scavenger receptor.
The intercellular transport of lipids through the circulatory system requires the packaging of these hydrophobic molecules into water-soluble carriers, called lipoproteins, and the regulated targeting of these lipoproteins to appropriate tissues by receptor-mediated pathways. The most well characterized lipoprotein receptor is the LDL receptor, which binds to apolipoproteins B-100 (apoB-100) and E (apoE), which are constituents of low density lipoprotein (LDL), the principal cholesteryl-ester transporter in human plasma, very low-density lipoprotein (VLDL), a triglyceride-rich carrier synthesized by the liver, intermediate-density lipoprotein (IDL), and catabolized chylomicrons (dietary triglyceride-rich carriers).
LDL receptors and most other mammalian cell-surface receptors that mediate binding and, in some cases, the endocytosis, adhesion, or signaling exhibit two common ligand-binding characteristics: high affinity and narrow specificity. However, two additional lipoprotein receptors have been identified which are characterized by high affinity and broad specificity: the macrophage scavenger receptors class A type I and type II. Scavenger receptors mediate the endocytosis of chemically modified lipoproteins, such as acetylated LDL (AcLDL) and oxidized LDL (OxLDL), and have been implicated in the pathogenesis of atherosclerosis (Krieger and Herz, 1994 Annu. Rev. Biochem. 63, 601–637; Brown and Goldstein, 1983 Annu. Rev. Biochem. 52, 223–261; Steinberg et al., 1989 N. Engl. J. Med. 320, 915–924). Macrophage scavenger receptors exhibit complex binding properties, including inhibition by a wide variety of polyanions, such as maleylated BSA (M-BSA) and certain polynucleotides and polysaccharides, as well as unusual ligand-cross competition (Freeman et al., 1991 Proc. Natl. Acad. Sci. U.S.A. 88, 4931–4935, Krieger and Herz, 1994). Several investigators have suggested that there may be at least three different classes of such receptors expressed on mammalian macrophages, including receptors which recognize either AcLDL or OxLDL, or both of these ligands (Sparrow et al., 1989 J. Biol. Chem. 264, 2599–2604; Arai et al., 1989 Biochem. Biophys. Res. Commun. 159, 1375–1382; Nagelkerke et al., 1983 J. Biol. Chem. 258, 12221–12227).
Krieger, et al., in PCT/US95/07721 “Class BI and CI Scavenger Receptors” Massachusetts Institute of Technology (“Krieger, et al.”), described the isolation and cloning of two distinct scavenger receptor type proteins having high affinity for modified lipoproteins and other ligands, SR-BI, an AcLDL and LDL binding scavenger receptor, which is distinct from the class A type I and type II macrophage scavenger receptors, and dSR-CI, a non-mammalian AcLDL binding scavenger receptor having high ligand affinity and broad specificity, isolated from Drosophila melanogaster. 
Krieger, et al. reported in PCT98/18463 by Massachusetts Institute of Technology that the SR-BI receptor is expressed principally in steroidogenic tissues and liver and appears to mediate HDL-transfer and uptake of cholesterol. Competitive binding studies show that SR-BI binds LDL, modified LDL, negatively charged phospholipid, and HDL. Direct binding studies show that SR-BI expressed in mammalian cells (for example, a varient of CHO cells) binds HDL, without cellular degradation of the HDL-apoprotein, and lipid is accumulated within cells expressing the receptor. These studies indicate that SR-BI play a major role in transfer of cholesterol from peripheral tissues, via HDL, into the liver and steroidogenic tissues, and that increased or decreased expression in the liver or other tissues may be useful in regulating uptake of cholesterol by cells expressing SR-BI, thereby decreasing levels in foam cells and deposition at sites involved in atherogenesis.
Infertility is a major problem, with a multitude of causes ranging in the female from physical blockage to hormonal imbalance to unknown causes. In most cases, women are treated initially using hormones to see if fertility is improved (for example, restoration of normal menstrual cycles, pregnancy, or resolution of fibroid cysts). Surgical intervention is then usually attempted, to removed blockages or cysts. There remain many women for whom such treatments are not effective.
It is therefore an object of the present invention to provide methods and reagents for identifying pharmaceutical compositions that can alter lipid levels mediated by SR-BI and thereby restore fertility to women in need thereof.
It is a further object of the present invention to provide pharmaceutical compositions that can alter lipid levels mediated by SR-BI and thereby restore fertility to women in need thereof.